This application represents a resubmission of a competing renewal application for a Specialized Program of Research Excellence (SPORE) in Kidney Cancer from the Kidney Cancer Program of Dana-Farber/Harvard Cancer Center (DF/HCC). The DF/HCC Kidney Cancer SPORE has been funded for two cycles since 2003. DF/HCC is comprised of the following institutions: Beth Israel-Deaconess Medical Center (BIDMC); Dana- Farber Cancer Institute (DFCI); Harvard Medical School; Harvard School of Public Health; Brigham and Women's Hospital; Massachusetts General Hospital (MGH); and Children's Hospital of Boston. In addition to the institutions in the DF/HCC, the Whitehead Institute at Massachusetts Institute of Technology and Georgetown-Lombardi Cancer Center (GLCC) are collaborating institutions in this grant. The DF/HCC Kidney Cancer SPORE has its administrative base at the BIDMC. Dr. David McDermott, who has led the DF/HCC Kidney Cancer Program and SPORE since 2012 is joined as SPORE Director by Dr. William Kaelin, a laboratory scientist at DFCI and Associate Director for Basic Science in the DF/HCC. Drs. McDermott and Kaelin report directly to Dr. Edward Benz, Director of DF/HCC and President of DFCI. The DF/HCC Kidney Cancer SPORE has a broad and deep talent base and there is extensive institutional commitment. We take advantage of a large patient population and cutting edge technologies that are available to us as part of DF/HCC. We propose 4 Projects which address critical problems in kidney cancer and have translational components. They focus on identifying effective strategies for targeting: HIF2?, the dominant oncogenic driver of clear-cell RCC (Project 1), angiogenesis inhibitor resistance mechanisms, which undermine the most commonly applied therapies (Project 2) and improving the therapeutic index of agents targeting the mTOR (Project 3) and immune checkpoint pathways (Project 4). The projects are supported by three Cores - an Administrative Core, a Biostatistics and Computational Biology Core, and a Tissue Acquisition, Pathology and Clinical Data Core. We also have a highly successful Career Development Program that selects talented physician scientists and mentors them to independence as well as a Developmental Projects Program that generates new ideas for the SPORE in the future. The existence of the SPORE has provided opportunities and incentives to extend basic science and clinical research ideas into the translational realm and facilitated the entry of young, as well as some seasoned, investigators into the kidney cancer field where they have made major contributions.